Vaccination of multiple myeloma patients with idiotype‐pulsed dendritic cells: immunological and clinical aspects

Abstract

Summary. Multiple myeloma (MM) is characterized by a clonal proliferation of malignant plasma cells in the bone marrow secreting a monoclonal immunoglobulin (paraprotein) with specific antigenic determinants, the idiotype (Id), which can be regarded as a tumour-associated antigen (TAA). In order to analyse the impact of a dendritic cell (DC)-based vaccine, 11 patients with advanced MM were treated with CD34 stem cell-derived dendritic cells that were pulsed with Id peptides. Subsequently, the patients received three boost immunizations every other week with a combination of Id and granulocyte±macrophage colonystimulating factor (GM-CSF) (nine patients) or with Id peptide-pulsed dendritic cells again (two patients). The treatment was well tolerated with no side-effects. The present clinical study was a proof of concept analysis of dendritic cell-based vaccines in MM. The capacity of the dendritic cells to activate idiotype-specific T cells was verified by in vitro stimulation experiments before the vaccination therapy. Immunological effects of the Id vaccination were analysed by monitoring changes in anti-idiotype antibody titres and idiotype-specific T-cell activity. After vaccination, three out of 10 analysed patients showed increased antiidiotype antibody serum titres, indicating the induction of an idiotype-specific humoral immune response. The idiotype-specific T-cell response analysed by ELISpot was increased in four out of 10 analysed patients after vaccination, and one patient had a decreased plasma cell infiltration in the bone marrow. In conclusion, five out of 11 patients showed a biological response after vaccination. Thus, our data indicate that immunotherapy with Id-pulsed DCs in MM patients is feasible and safe. DC generated from CD34 1 progenitor cells can serve as a natural adjuvant for the induction of clinically relevant humoral and cellular idiotype-specific immune responses in patients suffering from advanced MM.

Clinical implications of antigen transfer mechanisms from malignant to dendritic cells

“…The first observations were made in experimental myelomas, and it has been speculated that these types of mechanisms can be important in understanding the therapeutic effects of anti-idiotypic humoral responses in malignancies of lymphoid origin. Moreover, it has been repeatedly noted, even in clinical trials, that in vitro DC pulsing with either immunoglobulin alone or tumor idiotype conjugated with keyhole limpet hemocyanin (KLH ) can induce cellular immune responses in vivo upon reinfusion of the pulsed DC into the patient [101][102][103][104]. These results suggest that the Fc receptors expressed by DC may internalize tumor-specific idiotype-bearing immunoglobulins alone or as part of immunoconjugates (immunoglobulin chemically complexed to KLH).…”

In vivo cellular imaging of lymphocyte trafficking by MRI: A tumor model approach to cell‐based anticancer therapy

“…Immunotherapy can be used to induce an efficient specific response to solid tumors of the colon (2) and lung (3), or to hematopoietic cancers such as leukemia (4 -6), lymphoma (7,8), and myeloma (9). Cellular imaging techniques are being developed to track cell redistribution in vivo and to assess treatment efficacy in terms of tumor growth.…”

Idiotype protein-pulsed dendritic cells produce strong anti-myeloma effects after syngeneic stem cell transplantation in mice

“…25 Several clinical trials were initiated using pulsed dendritic cells derived from monocytes [26][27][28] or CD34 + progenitor cells. 29 Wen and coworkers 26 treated advanced-stage myeloma patients with idiotype-pulsed DC. Id-specific immune responses were generated, characterised by MHC-dependent T cell proliferative responses with cytokine release and the production of anti-Id antibodies.…”